Field of invention:
[0001] The present invention relates to a process for the manufacture pharmaceutically active
compounds and their intermediates, in particular to a process for making (2S, 3aS,
7aS)-1-[(2S)-2-[[(1S)-1-(ethoxycarbonyl) butyl] amino]-1-oxopropyl] octahydro-1
H-indole-2-carboxylic acid, commonly known as Perindopril, its salts like tert. butyl
amine salt and its novel intermediate compounds, specifically aralkyl perindopril
ester salts.
Background and Prior Art :
[0002] Perindopril (Formula IA) and its pharmaceutically acceptable salts, especially the
tert. butylamine salt (Formula IB), have valuable pharmacological properties. Their main
property lies in the inhibition of the enzyme that converts angiotensin I (or kininase
II), a precursor for formation of angiotensin II enzyme, thereby enabling on the one
hand prevention of the conversion of the decapeptide angiotensin I to the octapeptide
angiotensin II (vasoconstrictor) and on the other hand prevention of the degradation
of bradykinin (vasodilator) to inactive peptide. These two actions contribute to the
beneficial effects of perindopril or its salts in cardiovascular disorders, especially
arterial hypertension and cardiac insufficiency. The use of perindopril in these therapies
demands high purity of the final compound in a manufacturing operation.
[0003] Perindopril, its preparation and its therapeutic use were first described in European
Patent Specification No. 0049658.
[0004] An alternative route of synthesis for Perindopril has been reported in Tetrahedron
Letters 23, (16), 1677-1680, (1982), wherein the
tert. butyl ester of (2S, 3aS, 7aS)-octahydroindole-2-carboxylic acid was coupled with
N- [(S)-1-carboxybutyl]-(S)-alanine ethyl ester (Formula III) in presence of triethyl
amine, dicyclohexylcarbodiimide(DCC), and 1-hydroxy benzotriazole(HOBT) and subsequently
deprotecting the
tert. butyl ester protective group from the resultant intermediate. The
tert. butyl amine (erbumine) salt of perindopril was reported for the first time in the
above publication.
[0005] Subsequently, European patent No. 0308341 has disclosed a similar process for Perindopril
purported to be an industrial process by the reaction of (2S, 3aS, 7aS)-octahydroindole-2-carboxylic
acid esters of Formula II with N- [(S)-1-carboxybutyl]-(S)-alanine ethyl ester of
Formula III using triethylamine, DCC and HOBT to give the compound of Formula IV followed
by de-protection of the ester group selectively by methods known in the art to obtain
perindopril (Formula IA). The ester forming groups for (2S, 3aS, 7aS)-octahydroindole-2-carboxylic
acid ester are selected from benzyl, and alkyl groups. Perindopril erbumine salt (Formula
IB) is then obtained by combining
tert. butylamine with Perindopril (Formula IA).
[0006] However, the product obtained by the above process contains many impurities thereby
making the product isolation difficult even on laboratory scale, as also observed
by others, and the process improvement taking care of a part of the problems has been
the subject of patent applications No. US 2003 / 0069431 and WO 0364388.
[0007] The United States patent application 2003 / 0069431 describes a modified process
for the manufacture of Perindopril and its
tert. -butyl amine salt using the same reactants. It discloses the reaction of benzyl
ester of (2S, 3aS, 7aS)-octahydroindole-2-carboxylic acid with N- [(S)-1-carboxybutyl]-(S)-alanine
ethyl ester in solvent ethyl acetate, in presence of reduced molar quantities of HOBT,
DCC and in presence or absence of triethyl amine, whereby the impurities of Formula
VII & Formula VIII in perindopril are brought down to below 0.1 and 0.2% respectively
but with extra purifications.

[0008] According to the process mentioned in patent application No. WO 03/064388, the compound
of Formula III is N-protected by suitable carbonic acid derivatives. The carboxylic
acid group is then converted into its acid chloride, followed by its reaction with
octahydroindole-2-carboxylic acid, yielding perindopril of better purity. It also
avoids use of DCC. Various other process-patents such as EP1371659. EP1380591, EP1380590,
EP 1362864, EP1367061 are published, and claimed to minimize the problems associated
with prior art i.e. purity of Perindopril. In these reports, the route of synthesis
and the intermediates are different than the processes, discussed above.

[0009] A thorough study of prior art indicates that the process route disclosed in Tetrahedron
Letters 1982, 23(16), 1677-1680, is the best suited as an industrial route and comparatively
more economical to produce Perindopril or its erbumine salt, provided it avoids the
formation of impurities as well as eliminates need for additional purification steps.
Patent application WO 01/58868 addressed this problem to some extent by reducing two
impurities having Formula VII and VIII to give improved quality of the product.
[0010] The processes mentioned in patents EP 0308341 and WO 01/58868 describe the use of
ethyl acetate as a solvent in the amino acid coupling step. Under the conditions of
coupling, one major impurity, viz. N-acetyl (2S, 3aS, 7aS)-octahydroindole-2-carboxylic
acid benzyl ester (Formula V), is formed. Formation of this impurity has been identified
to be associated with the use of ethyl acetate as solvent. The reason being ethyl
acetate acting as acylating agent to form the impurity of Formula V. Removal of this
impurity is very difficult at this stago, as the nature of the impurity and the resultant
coupled products is very similar. It is also difficult to remove the impurity in the
next step i.e. debenzylation. The coupled product (Formula IV) gives Perindopril (Formula
IA) whereas compound of Formula V also gets debenzylated to form N-acetyl (2S, 3aS,
7aS) octahydroindole-2-carboxylic acid (Formula VI), which again contaminates as an
impurity in final perindopril. Since the heterocyclic part containing the carboxylic
acid group is present in both Perindopril (Formula IA) and in this impurity (Formula
VI) and due to this, during salt formation of Perindopril with
tert. - butylamine, compound of Formula VI invariably remains contaminated with the final
perinodpril erbumine salt (Formula IB).

[0011] Yet another report (WO 2004/099138), disclosed a debenzylation of benzylperindopril
in presence of tert.butylamine to directly isolate perindopril erbumine salt after
debenzylation. Although this process reduces one process operation, i.e., tort. butylamine
salt formation, but the process does not take care of impurities generated in the
peptide coupling stage, i.e., the benzyl perindopril formation and there is no report
on the effective means for purification of the product. This again leads to repeated
purification of the final perindopril erbumine salt to get a pharmaceutically acceptable
purity.
[0012] Although the impurities formation can be controlled to some extent by varying solvents
or by changing the coupling catalysts, but the problems of isolation & purification
of the benzyl perindopril as well as resulting perindopril still remains. Since there
is no effective means for a purification of benzyl perindopril, which is an oily product,
it is difficult to ensure the purity of benzyl perindopril and thus that of perindopril.
This eventually necessitates extra purifications in the tert. butyl amine salt formation
stage, incurring heavy losses of the final product, perindopril erbumine .
[0013] From the above it is clear the key to the success of the process is the purity of
benzyl ester of perindopril obtained after the coupling of intermediate compounds
of Formula II & III. The present invention directs to address these problems, where
a means for the isolation of benzylperindopril of Formula IV is provided to get rid
of the impurities resulting from the peptide coupling reaction and thereby reflecting
in high purity of perindopril erbumine, the subject of the present invention.
Objective of the present invention
[0014] The major objective of the present invention is to provide an industrial process,
which gives high purity perindopril or its salts, and improvements thereof. A further
objective is to provide suitable intermediate compounds useful for the synthesis of
perindopril or its salt of high purity. Yet another objective is to provide a suitable
process & methods for purification of benzyl perindopril to get higher purity in order
to use in the synthesis.
Summary of the invention
[0015] Accordingly, in one aspect, the present invention provides novel aralkyl perindopril
ester salts represented by the general formula IVA for the synthesis of perindopril
erbumine. The acids capable of forming the salt of aralkyl ester of perindopril include
organic (chiral & achiral) and inorganic acids. The examples of new salts of the present
invention include, but not limited to, benzylperindopril phthalic acid salt, benzylperindopril
tartaric acid salt, benzylperindopril phosphate, benzyl perindopril camphor sulphonate,
benzylperindopril oxalate, benzylperindopril citrate, benzylperindopril (-)-di-
p-toluoyl tartarate, benzylperindopril (+)-di-
p-toluoyl tartarate , benzylperindopril (±)-dibenzoyltartarate or the like.
[0016] In a further aspect, the present invention relates to use of novel intermediate salts
of aralkyl perindopril ester of the present invention for the synthesis of perindopril
erbumine in pharmaceutically acceptable purity & higher yields.
[0017] In one more aspect, the present invention provides a process for preparation of aralkyl
perindopril ester salts of Formula IVA, which process involves condensation of an
aralkyl ester of octahydroindole of Formula IIR or its acid salt with the compound
of Formula III in presence of a coupling reagent like DCC, triethyl amine and HOBT
in a non-reactive solvent like methylene chloride to form a reaction mixture including
aralkyl ester of perindopril, and treating the reaction mass containing aralkyl perindopril
ester with an acid capable of forming a salt and isolating the aralkyl perindopril
ester salt from the reaction mass as solid in higher HPLC purity. The aralkyl perindopril
ester salt can be separated from the mixture by conventional means such as filtration,
extraction, precipitation, centrifugation etc. and can be optionally purified at ambient
or elevated temperatures.
[0018] In another embodiment of the present invention, the resulting intermediate aralkyl
perindopril ester salt (Formula IVA) is deprotected under hydrogenation conditions
using a metal catalyst such as palladium/C in solvents such as C1 to C4 straight or
branched chain alcohols. The product is isolated as corresponding perindopril acid
addition salt or either neutralized with a base to isolate free perindopril or directly
converted to tertiary butylamine salt, i.e., perindopril erbumine.
[0019] In yet another embodiment of the present invention the perindopril erbumine salt
is formed by combining the tert.butyl amine base with perindopril free acid or its
acid addition salt in aqueous medium. The erbumine salt is isolated by extracting
using a water immiscible organic solvent, concentration of the extraction solvent
and optional leaching with a second organic solvent to obtain perindopril erumine
in pure form.
[0020] In yet another aspect the invention relates to perindopril prepared according to
the process of the present invention.
[0021] In a further aspect, the present invention provides pharmaceutical compositions containing
high purity perindopril or its erbumine salt prepared according to the novel process
described herein. The pharmaceutical compositions may contain additional ingredients
commonly used in the preparation of such dosage forms such as fillers, binders, lubricants,
stabilizers, disintegrants etc. The dosage forms may include tablets, capsules, lozenges,
oral solutions/suspensions and injectables.
Detailed description
[0022] The present invention provides a novel process for preparation of perindopril erbumine
salt of Formula IB in pure form, which ameliorates most of the problems associated
with reported industrial processes. The method is simple, operates in moderate reaction
conditions, yields high purity perindopril erbumine and easy to operate on industrial
scale. A preferred embodiment of the present process is illustrated in scheme 1, which
is presented below:

[0023] In scheme 1, in Formula IIA, IVB & IVA, the R group is the corresponding substituted/
un-substituted aralkyl groups (the terminology arylalkyl means to be synonym of aralkyl
in this specification) that can be in each case substituted or un-substituted phenyl
methyl groups. The preferred aralkyl groups are benzyl, mono- or di-, or tri- alkyl
or alkoxy or halo or nitro substituted benzyl, diphenyl methyl, or triphenylmethyl
or the like. Although there is no special limitation, the preferred aralkyl group
is benzyl. For the purposes of illustration the 'R' group is explained with respect
to benzyl group in the description detailed below.
[0024] In the scheme I, in Formula IVA the acid is selected from chiral or achiral organic
acid and inorganic acids. If not stated specifically, the acids capable of forming
salts of Formula IV may mono-basic, dibasic, or polybasic acids.
[0025] The preferred acids are selected from, but not limited to, phthalic acid, tartaric
acid, di-
p-toluoyl tartaric acid, dibenzoyl tartaric acid, camphor sulphonic acid, oxalic acid,
citric acid, phosphoric acid and para-toluenesulphonic acid. The most preferred acid
is oxalic acid or di-
p-toluoyl tartaric acid. Consequently the above acid salts of perindopril alkyl/aralkyl
ester of Formula IVA, exemplary salts include benzylperindopril phthalic acid, benzylperindopril
tartrate, benzylperindopril phosphate, benzyl perindopril camphor sulphonate, benzylperindopril
oxalate, benzylperindopril citrate, benzylperindopril (-)-di-
p-toluoyltartarate, benzylperindopril (+)-di-
p-toluoyl tartarate , benzylperindopril (±)-dibenzoyl tartarate, of the present invention
are novel and forms part of the present invention.
[0026] Hence the present invention provides the novel salts of alkyl/aralky perinopril ester
(Formula IVA) as intermediates for preparing perindopril or its salts in higher purity
and yields. The process for perindopril or its salts of the present invention is further
described in detail below:
[0027] In a preferred embodiment of the process of the present invention, a compound of
Formula IA or IB is prepared by the process comprising, a) reacting octahydrocarboxyindole
carboxylic acid ester (Formula IIA, where R is alkyl/aralkyl group) with a compound
of Formula III, to obtain a compound of Formula IVB ; and
b) converting said compound to an acid addition salt of Formula IVA by reacting it
with an acid capable of forming a salt and isolating the said salt of Formula IVA
in substantially pure form, and c) further deprotecting the compound of Formula IVA
to recover salt of perindopril with corresponding acid and further coverting to the
product of Formula IA or IB.
[0028] In the process, in a first step, the octahydroindole carboxylic acid ester of Formula
IIA or its acid salt is reacted with the alanine derivative of Formula III in presence
of peptide coupling reagents like DCC, HOBT and with or without a base like triethylamine
. The acid salt of octahydroindole carboxylic ester is preferably a
para-toluene sulphonate salt. The coupling reaction is preferably carried out in a non-reactive
peptide coupling solvents selected from chlorinated hydrocarbon solvents, hydrocarbon
solvents or polar aprotic solvents or ether solvents.
[0029] In a preferred embodiment of the present process, the para-toluene sulphonate salt
of compound of Formula IIA is coupled with alanine derivative of Formula III in presence
of DCC, HOBT and triethyl amine in solvents like methylene dichloride or the like.
The reaction is preferably carried out by mixing the components in the non-reactive
solvent media at a temperature of about 10 to 35 °C for a period of 12 to 24 hours.
In the process the molar amount of reactants and reagents are optimized in order to
minimize the impurity generation in the coupling stage. The preferred molar ratio
of compound of Formula III to compound of Formula IIA is about 1.0 to 2.0 wherein
the amounts of reagents DCC & HOBT are in a molar amount ranging from about 1.0 to
2.0 moles relative to compound of Formula IIA. Triethyl amine is used in molar proportion
of 1.0 to 3.0 relative to compound of Formula IIA.
[0030] After completion of reaction the reaction mass containing aralkylperindopril ester
is filtered to remove the by-product (dicyclohexyl urea). The remaining traces of
dicylohexylurea from the reaction mass are removed by concentrating reaction solvent,
dissolving the obtained residue in non-polar solvents like hexane, cyclohexane or
diisopropyl ether and filtering out the residual dicyclohexylurea.
[0031] In the second step of the present invention, the oily intermediate aralkyl ester
of perindopril obtained is combined with an organic or inorganic acid capable of forming
a salt. The salt formation is preferably carried out in a solvent such as methylene
chloride, or ketone solvents like acetone, or C1 to C4 alcohol, or the like.. The
organic acid used for the isolation of aralkyl perindopril ester salt is selected
from, but not limited to, phthalic acid, L-(+)-tartaric acid, di-
p-toluoyl trataric acid, (±)-dibenzoyl tartaric acid, camphor sulphonic acid, oxalic
acid, citric acid, phorsphoric acid, sulphonic acid such as methane sulphonic acid
and
para-toluenesulphonic acid. The solvent especially useful during the salt formation includos
alcohols, ethers, acetronitrile, ketonic solvents such as acetone, hydrocarbon solvents,
and chlorinated hydrocarbon solvents,
[0032] In the above process, a sufficient quantity of acid is used to form the salt and
is preferably in a molar amount ranging from 1 to 2 moles. Typically a slight excess
of acid is used to ensure the complete salt formation and it is preferably about 1.0
to 1.8 moles relative to the starting compound of Formula IVB. The salts are preferably
formed at ambient temperature conditions by agitating the mixture in the solvent for
sufficient period of time or by means of heating the mixture in the solvent for sufficient
period of time.
[0033] The aralkylperindopril ester salt (Formula IVA) is then isolated from the reaction
solvent, and if required, further purified by conventional means like crystallization,
or precipitating out using an anti-solvent & recrystallization or solvent evaporation
and slurrification in a second solvent. Anti-solvent herein means a solvent where
the required substance (solute) is inolublo or sparingly soluble so that the addition
of such solvent brings out the product of choice from the more soluble solvent solution.
The solvents especially useful for this purpose in this invention are hydrocarbon
solvents like hexane, cyclohexane, toluene or the like.
[0034] The precipitated aralkyl perindopril ester salt can then be separated from the solvent(s)
by conventional means such as filtration, centrifugation etc. and can be optionally
dried at ambient temperatures. In most of the cases the purity of the isolated aralkyl
perindopril ester salt exceeds 99 % sufficient enough to produce pure perindopril
erbumine. This higher purity of the intermediate essentially avoids further purification
of perindopril or its salt after de-protection and thereby reduces subsequent losses.
Moreover this improvement facilitates the isolation of either perindopril or perindopril
salts in pure crystalline form.
[0035] Finally, according to the present invention, the aralkyl perindpril ester salt (IVA)
is de-protected using conventional reagents to give perindopril or its salts. In a
preferred embodiment of the invention, the isolated acid salt of aralkyl perindopril
ester is hydrogenated using hydrogenation catalyst like palladium, to form perindopril
or its salts. The deprotection process is preferably performed in a solvent medium
selected from, but not limited to, C1 to C4 straight or branched chain alcohol or
their mixture. The removal of aralkyl ester group is effected at a hydrogenation temperature
in the range of 25 to 40°C and under a hydrogen pressure of about 1 to 6 atmospheres.
After deprotection the catalyst is removed by filtration, the filtrate after concentration
gives the acid salt of perindopril. The acid salt of perindopril can be isolated after
the deprotection in solid form or is carried forward for the erbumine salt formation
directly in the extraction solvent.
[0036] The perindopril erbumine (Formula IA) is then prepared by cleavage of this salt using
a base in an aqueous medium and extracting perindopril with the help of an organic
solvent. The perindopril so obtained, after evaporation of extraction solvent, is
combined with tertiary butylamine in a suitable solvent such as ethyl acetate, MDC
or alcohols etc and crystallized to obtain perindopril erbumine salt. The base preferably
used to break the perindopril acid salt is selected from alkali metal carbonate or
bicarbonates or trialkyl amines.
[0037] Alternately, the perindopril acid salt obtained above is treated with an excess amount
of tertiary butylamine in an aqueous medium. Perindopril erbumine salt thus obtained
is then directly extracted with an organic solvent such as methylene chloride or the
like. The pure perindopril erbumine salt (Formula IB) is then isolated either by removing
the solvent or changing the extraction solvent with a second solvent such as ethyl
acetate and crystallizing pure perindopril by applying cooling or chilling. The process
of precipitation is also being carried out in a mixture of first and second solvent
and in that case the second solvent acts as an anti-solvent. Anti-solvent herein means
a solvent where the perindopril erbumine has less or poor or no solubility.
[0038] The precipitated perindopril erbumine salt can then be separated from the solvent
mixture by conventional means such as filtration, centrifugation etc. and can be optionally
dried at ambient or elevated temperatures. The purity of perindopril erbumine is at
least 99.5% by following this process.
[0039] In a process variant, according to the invention, in the hydrogenation step of aralkyl
perindopril ester salt (Formula IVA), a hydrogenation composition is made by combining
aralkyl perindopril ester salt, a base, a palladium catalyst and an organic solvent,
which is subjected to hydrogenation conditions. In this step the base is preferably
tertiary butyl amine and is used in sufficient quantity to form the perinopril erbumine
salt after hydrogenation. The base is preferably used in a molar amounts ranging from
1 to 4 moles equivalents relative to the aralkyl perindopril ester salt. This process
variant has advantages that it either neutralizes the reaction mixture to liberate
perindopril free acid or make the perindopril erbumine salt directly without having
the need of an additional step for salt formation. The perindopril erbumine salt obtained
is further crystallized from ethyl acetate.
[0040] The advantage of making an acid addition salt of aralkyl perindopril according to
this invention is that various impurities, both polar and non-polar, can be removed
very efficiently. Additionally, this isolation of intermediate in crystalline form
facilitates the removal of other chiral isomers and yields the benzylperindolpril
ester salt and final perindoprilate or perindopril erburnine in higher chiral purity.
[0041] The following examples, which include preferred embodiments, will serve to illustrate
the practice of this invention, it being understood that the particulars shown are
by way of example and for purpose of illustrative discussion of preferred embodiments
of the invention.
Examples:
Example 1: (2S, 3aS, 7aS)-1-{(2S)-2-(1S)-1-(Ethoxycarbonyl)-butylamino]-propionyl}-octahydro-1H-indole-2-benzyl carboxylate (Benzyl perindopril).
[0042] To a suspension of 100 gm of para-toluene sulfonate of benzyl ester of (2S, 3aS,
7aS)-octahydroindole-2-carboxylic acid in 2.0 litre of methylene chloride, 70.3 gm
of triethylamine is added at 20-25°C. After stirring, 34.5 gm of 1-hydroxybenzotriazole,
60.4gm. of N-[(S)-carbethoxy-1-butyl]1(S)-alanine and 57.4gm. of dicyclohexylcarbodiimide
were added in the same sequence at the interval of about 15 minutes. The heterogeneous
mass is stirred till completion of reaction at 20-25°C. Then the dicyclohexyl urea
is filtered and the filtrate is washed with water. The solvent is removed under vacuum.
Approx. 1.0 litre of diisopropyl ether is added to the above mass and stirred for
about 15 minutes, filtered, solvent distilled under vacuum to give 105gm. (99%) product
in the form of oil (purity 90%).
Example 2: Benzylperindopril oxalate
[0043] In a reaction flask, 20 gm of the oil obtained as per Example 1 was taken in 60 ml
dichloromethane.. 7.07 gm of oxalic acid was added and mixed at ambient temperature
for about 2-3 hours. To this mixture 500ml of hexane was added and further maintained
under stirring for about 2 hours. The solid obtained was filtered and dried to obtain
24.5 gm of oxalic acid salt of benzyl perindopril. (melting point 108-118° C).
Example 3 : Perindopril oxalate
[0044] 15 gm of oxalic acid salt of benzyl perindopril obtained as per Example 2 was taken
in 150 ml ethanol in an autoclave. 1.5 gm of 5% Pd/C catalyst was charged to the autoclave
and debenzylation was carried out at about 5 kg/cm
2 hydrogen pressure at around 30° C. Debenzylation was completed in 3-4 hours and then
the catalyst was filtered and the filtrate was distilled to remove solvent to obtain
12.0 gm of oxalic acid salt of perindopril.
Example 4: Perindopril erbumine
[0045] 10 gm of oxalic acid salt of benzyl perindopril obtained as per Example 2 was taken
in 200 ml ethanol and mixed with 5.0 gm
tert.butyl amine. The mixture was charged to an autoclave. 1.0 gm of 5% Pd/C catalyst was
charged to the autoclave and debenzylation was carried out at about 5 kg/cm
2 hydrogen pressure at around 30°C. Debenzylation was completed in about 3 hours and
then the catalyst and insoluble salt were filtered and the filtrate was distilled
to remove solvent. The residue was crystallized from ethyl acetate to obtain 5.0 gm
of Perindopril erbumine .
Example 5: Perindopril erbumine
[0046] To 10 gm of oxalic acid salt of perindopril obtained as per Example 3, 100 ml of
dichloromethane was added and mixed with 9.3 ml of
tert.butylamine. Upon agitation a thick mass was precipitated out which was filtered off.
The filtrate obtained was then distilled to remove solvent. The solid obtained was
dissolved in 150 ml of ethyl acetate at reflux temperature and then cooled to 30 °
C. The precipitate was filtered to obtain 4.9 gm of perindopril erbumine.
Example 6: Perindopril erbumine
[0047] To 10 gm of oxalic acid salt of perindopril obtained as per Example 3, 30 ml water
was added. To this 8.0 gm of
tert-butylamine was added. The perindopril erbumine salt obtained was extracted into dichloromethane
from the aqueous layer. The orgainc layer was then distilled to remove solvent. The
residue obtained was dissolved in 100 ml ethyl acetate at reflux temperature. The
solution was cooled and filtered to give 4.8 gm of perindopril erbumine.
Example 7: Perindopril erbumine
[0048] 20 gm of oxalic acid salt of benzyl perindopril obtained as per Example 2 was taken
in 200 ml ethanol in an autoclave. 2.0 gm of 5% Pd/C catalyst was charged to the autoclave
and debenzylation was carried out at about 5 kg/cm
2 hydrogen pressure at around 30
0C, Debenzylation was completed in about 3 hours and then the catalyst was filtered
off. To the filtrate 12 gm of
tert.butyl amine was added and the precipitated salt was filtered. The filtrate was distilled
to remove solvent and the residue was crystallized from 200 ml of ethyl acetate to
obtain 10.0 gm of Perindopril erbumine
Example 8: (-)-DPTTA salt of benzyl perindopril
[0049] In the reaction flask, 20 gm of the oil obtained as per Example 1 was taken in 200
ml acetone. To this 20 gm of (-)-di-
p-toluoyl tartaric acid [(-)-DPTTA] was added and mixed at ambient temperature for
about 2-3 hours. Then acetone was distilled and 400 ml of hexane was added and further
maintained under stirring for 2 hours. The precipitate was filtered and dried to obtain
38.9 gm of (-)-di-
p-toluoyl tartaric acid salt of benzyl perindopril i.e. (-)-DPTTA salt of benzyl perindopril
(melting point 69-74°C).
Example 9: Perindopril (-)-DPTTA salt
[0050] 15 gm of (-)-DPTTA salt of benzyl perindopril obtained as per Example 8 was taken
in 150 ml ethanol in an autoclave. 1.5 gm of 5% Pd/C catalyst was charged in the autoclave
and debenzylation was carried out at about 5 kg/cm
2 hydrogen pressure at ambient temperature. Debenzylation was completed in about 3
hours and then the catalyst was filtered and the filtrate was distilled to remove
solvent. 150 ml of cyclohexane was added to the residue and a slurry was prepared
in cyclohexane and stirred for 2 hours. The solid was filtered to obtain 13.5 gm of
(-)-di-
p-toluoyl tartaric acid salt of perindopril i.e. (-)-DPTTA salt of perindopril . The
crude product was crystallized from ethyl acetate-hexane mixture (1:1.5) to obtain
9.0 gm of pure (-)-di-
p-toluoyl tartaric acid salt of perindopril i.e. (-)-DPTTA salt of perindopril. (melting
point 150-153°C).
[0051] Similar to Example 6, perindopril erbumine was prepared from 10 gm of (-)-DPTTA salt
of perindopril obtained as per above example (yield 3.2 gm).
Example 10: (+)-DPTTA salt of benzylperindopril
[0052] In the reaction flask, 20 gm of the oil obtained as per Example 1 was taken in 200
ml acetone. To this 20 gm of (+)-di-
p-toluoyl tartaric acid [(+)-DPTTA] was added and mixed at ambient temperature for
about 2-3 hours. Then acetone was distilled and 400 ml of hexane was added and further
maintained under stirring for 2 hours. The precipitate was filtered and dried to obtain
38.9 gm of (+)-di-
p-toluoyl tartaric acid salt of benzyl perindopril i.e. (+)-DPTTA salt of benzyl perindopril
Example 11: perindopril-(+)-DPTTA salt
[0053] 20 gm of (+)-DPTTA salt of benzyl perindopril obtained as per Example 10 was taken
in 200 ml ethanol in an autoclave. 2.0 gm of 5% Pd/C catalyst was charged in the autoclave
and debenzylation was carried out at about 5 kg/cm
2 hydrogen pressure at ambient temperature. Debenzylation was completed in about 3
hours and then the catalyst was filtered and the filtrate was distilled to remove
solvent. 200 ml of cyclohexane was added into the residue and a slurry was made in
cyclohexane and stirred for 2 hours. The solid was filtered to obtain 16.8 gm of (+)-di-
p-toluoyl tartaric acid salt of perindopril i.e. (+)-DPTTA salt of perindopril (melting
point 86-92°C).
Example 12: (±)-DBTA salt of benzyl perindopril
[0054] In the reaction flask, 15 gm of the oil obtained as per Example 1 was taken in 150
ml of dichloromethane.. To this 14 gm of (±)-dibenzoyl tartaric acid (DBTA) was added
and mixed at ambient temperature for about 2-3 hours. Dichloromethane was distilled
and 400 ml of hexane was added and further maintained under stirring for 2 hours.
The precipitate was filtered and dried to obtain 29 gm of (±)-dibenzoyl tartaric acid
salt of benzyl perindopril i.e. (±)-DBTA salt of benzyl perindopril
Example 13: Perindopril-(±)-DBTA salt
[0055] 15 gm of (±)-DBTA salt of benzyl perindopril obtained as per Example 12 was taken
in 150 ethanol in an autoclave. 1.5 gm of 5%Pd/C catalyst was charged to the autoclave
and debenzylation was carried out at about 5 kg/cm
2 hydrogen pressure at ambient temperature. Debenzylation was completed in about 3
hours. The catalyst was filtered and the filtrate was distilled to remove solvent
to obtain 13.4 gm of (±)-dibenzoyl tartaric acid salt of perindopril i.e. (±)-DBTA
salt of perindopril
Example 14: Perindopril tartarate
[0056]
(a) In the reaction flask, 10 gm of the oil obtained as per Example 1 was taken in
150 ml of acetone. To this 3.6 gm of L-(+)-tartaric acid was added and mixed at reflux
temperature for about 2-3 hours. Acetone was distilled to obtain 13.5 gm of tartaric
acid salt of benzyl perindopril.
(b) 9.0 gm of tartaric acid salt of benzyl perindopril obtained above was taken in
100 ml ethanol in an autoclave. 1.5 gm of 5%Pd/C catalyst was charged to the autoclave
and debenzylation was carried out at about 5 kg/cm2 hydrogen pressure at ambient temperature. Debenzylation was completed in about 3
hours. The catalyst was filtered and the filtrate was distilled to remove solvent
to obtain 7.5 gm of tartaric acid salt of perindopril.
Example 15: Perindopril from benzylperindoprilphosphate
[0057]
(a) In the reaction flask, 25 gm of the oil obtained as per Example 1 was taken in
250 ml acetone. To this 7.5 gm of ortho phosphoric acid was added and mixed at ambient
temperature for about 2-3 hours. Then acetone was distilled out to obtain 31 gm of
phosphate salt of benzyl perindopril..
(b) 30 gm of phosphate salt of benzyl perindopril obtained above was taken in 300
ml of ethanol and charged in an autoclave. 3 gm of 5% Pd/C catalyst was charged to
the autoclave and debenzylation was carried out at about 5 kg/cm2 hydrogen pressure at ambient temperature. Debenzylation was completed in about 3
hours, then the catalyst was filtered and the filterate was distilled to obtain 25.3
gm of phosphate salt of perindopril.
(c) 7.0 gm of of phosphate salt of perindopril obtained above was taken in 21 ml of
water. To this 6.7 ml of tert. butyl amine was added. It was stirred for 1 hour at ambient temperature and then
perindopril erbumine was extracted in dichloromethane. The solvent was distilled and
the residue obtained was dissolved in 75 ml ethyl acetate at reflux temperature. The
solution was cooled and precipitated solid was filtered to get 3.8 gm of perindopril
erbumine.
1. A compound of general formula IVA,

wherein R is selected from substituted or unsubstituted aralkyl (arylalkyl) groups;
and HA represents an acid capable of forming a salt.
2. A compound according to claim 1 wherein R is a substituted or unsubstituted phenyl
methyl group.
3. A compound according to claim 1 or claim 2 wherein R is selected from benzyl, mono-,
di-, or tri- alkyl, alkoxy, halo or nitro substituted benzyl, diphenyl methyl, or
triphenylmethyl or derivatives thereof.
4. A salt of a compound according to any one of claims 1 to 3.
5. A salt according to claim 4 being: benzylperindopril phthalic acid salt, benzylperindopril
tartaric acid salt, benzylperindopril phosphate, benzyl perindopril camphor sulphonate,
benzylperindopril oxalate, benzylperindopril citrate, benzylperindopril (-)-di-p-toluoyl tartarate, benzylperindopril (+)-di-p-toluoyl tartarate , or benzylperindopril (±)-dibenzoyltartarate.
6. A process for preparation of perindopril or its salts comprising the steps of
i) preparing a crudo aralkyl perindopril of Formula IV;

wherein R has the meaning assigned in any one of claims 1 to 3;
ii) converting the said ester into an organic acid salt of Formula IVA; and
iii) removing the arylalkylester group from said ester salt to provide either perindopril,
or its salt.
7. A process according to claim 6, wherein the step 6(i) comprises the following steps:
a) preparing a reaction mixture containing aralkyl perindopril ester by mixing
i) a compound of Formula II either as para-toluene sulphonate salt or free base, wherein R is as defined in claim 6,

ii) a compound of Formula III,

iii) one or more non-reactive peptide coupling solvents, and
iv) a catalyst combination selected from DCC & HOBT; optionally an organic base; and
b) isolating crude oily aralkyl perindopril ester.
8. A process according to claim 6 or claim 7, wherein the step 6(ii) comprises the following
steps:
c) treating the crude oily perindopril aralkyl ester with an acid in a solvent; and
d) isolating the corresponding acid salt of said perindopril aralkyl ester of sufficient
purity in solid form.
9. A process according to any one of claims 6 to 8, wherein the step 6(iii) comprises
the following steps:
e) hydrogenating the perindopril aralkyl ester acid salt either directly or in presence
of a base
OR
hydrogenating the free perindopril aralkyl ester obtained after treatment with a base;
and
f) isolating perindopril or its salt from the hydrogenation mass.
10. The process according to claim 7, wherein the organic peptide coupling solvent is
selected from a chlorinated hydrocarbon solvents, hydrocarbon solvents or polar aprotic
solvents or ether solvents.
11. The process according to claim 10, wherein the solvent is methylene chloride.
12. The process according to claim 7, wherein the organic base is triethylamine.
13. The process according to claim 8, wherein the acid is selected from phthalic acid,
tartaric acid, di-p-toluoyl tartaric acid, dibenzoyl tartaric acid, camphor sulphonic acid, oxalic acid,
citric acid, phosphoric acid and para-toluenesulphonic acid.
14. The process according to claim 8, wherein the solvent is methylene chloride, or ketone
solvents like acetone, or C1 to C4 alcohol, water or the like.
15. The process according to claim 9, wherein the aralkyl perindopril ester salt of Formula-IVA
is hydrogenated in presence of palladium catalyst in the absence of a base.
16. The process according to claim 15, wherein the perindopril is isolated as acid salt.
17. The process according to claim 16, wherein the acid salt of perindopril is further
converted to perindopril erbumine.
18. The process according to claim 9, wherein the hydrogenation of aralkyl perindopril
ester is effected in presence of an organic base.
19. The process according to claim 18, wherein the organic base is tert-butylamine.
20. The process according to claim 19, wherein the perindopril is isolated as perindopril
erbumine.
21. The process according to claim 17 or 20, wherein the perindopril erbumine is isolated
by an extractive work-up comprising
i) removing the hydrogenation catalyst from the hydrogenation mass;
ii) removing the hydrogenation solvent;
iii) dissolving the residue in water;
iv) extracting the perindopril erbumine from water in an organic solvent; and
v) isolating perindopril erbumine by methods such as evaporation or precipitation
by addition of an anti-solvent.
22. The process according to claim 21, wherein the extraction solvent is methylene chloride
or ethyl acetate.
23. Perindopril phthalic acid salt, perindopril tartaric acid salt, perindopril phosphate,
perindopril camphor sulphonate, perindopril oxalate, perindopril citrate, perindopril-
(-)-di-p-toluoyl tartarate, perindopril (+)-di-p-toluoyl tartarate , and perindopril (±)-dibenzoyltartarate.